The inventions described below relate to site specific delivery of therapeutic agents, structures and catheter systems to achieve site specific delivery of therapeutic agents, and means for implanting and using these systems to enable delivery of therapeutic agents to the body.
These systems also have importance for new procedures that have been called percutaneous transmyocardial revascularization or PTMR.
It is possible to identify particular sites within the myocardium which may benefit from local drug release therapy. Examples of problematic tissue which may benefit from local drug release therapy are ischemic sites and arrhythmogenic sites. Different means and methods for delivering agents to these sites will be disclosed in detail. These specific discussions should in no way limit the scope of the devices disclosed for treating other tissues with other agents.
Ischemic Sites
Ischemic tissue is characterized by limited metabolic processes which causes poor functionality. The metabolism is limited because the tissue lacks oxygen, nutrients, and means for disposing of wastes. In turn this hinders the normal functioning of the heart cells or myocytes in an ischemic region. If an ischemic, or damaged, region of the heart does not receive enough nutrients to sustain the myocytes they are said to die, and the tissue is said to become infarcted. Ischemia is reversible, such that cells may return to normal function once they receive the proper nutrients. Infarction is irreversible.
A number of methods have been developed to treat ischemic regions in the heart. Noninvasive systemic delivery of anti-ischemic agents such as nitrates or vasodilators allows the heart to work less by reducing vascular resistance. Some vascular obstructions are treated by the systemic delivery of pharmacological agents such as TPA, urokinase, or antithrombolytics which can break up the obstruction. Catheter based techniques to remove the vascular obstructions such as percutaneous transluminal coronary angioplasty (PTCA), atherectomy devices, and stents can increase myocardial perfusion. More drastic, but very reliable procedures such as coronary artery bypass surgery can also be performed. All of these techniques treat the root cause of poor perfusion.
It should be noted that these therapies are primarily for the treatment of large vessel disease, and that many patients suffer from poor perfusion within many of the smaller vessels. These smaller vessels cannot be treated with conventional therapies.
The delivery of angiogenic growth factors to the heart via the coronary arteries by catheter techniques, or by implantable controlled release matrices, can create new capillary vascular growth within the myocardium. Recent work has shown substantial increases in muscular flow in a variety of in vivo experimental models with growth factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and acidic fibroblast growth factor (aFGF). The methods of delivering these agents to the heart have included implantable controlled release matrices such as ethylene vinyl acetate copolymer (EVAC), and sequential bolus delivery into the coronary arteries. Recently similar techniques have been attempted in peripheral vessels in human patients with the primary difficulty being systemic effects of the agents delivered. xe2x80x9cAngiogenic agentsxe2x80x9d and xe2x80x9cendothelial agentsxe2x80x9d are active agents that promote angiogenesis and/or endothelial cell growth, or if applicable, vasculogenesis. This would include factors such as those discussed that accelerate wound healing such as growth hormone, insulin like growth factor-I (IGF-I), VEGF, VIGF, PDGF, epidermal growth factor (EGF), CTGF and members of its family, FGF, TGF-a and TGF B. The most widely recognized angiogenic agents include the following: VEGF-165, VEGF-121, VEGF-145, FGF-2, FGF-I, Transforming Growth Factor (TGF-B), Tumor Necrosis Factor a (TMF a), Tumor Necrosis Factor B (TMF B), Angiogenin, Interleukin-8, Proliferin, Prostaglandins (PGE), Placental Growth factor, Granulocyte Growth Factor, Platelet Derived Endothilail Cell Growth Factor, Hepatocyte Growth Factor, DEL-1, Angiostatin-1 and Pleiotrophin.
xe2x80x9cAngiostatic agentsxe2x80x9d are active agents that inhibit angiogenesis or vasculogenesis or otherwise inhibit or prevent growth of cancer cells. Examples include antibodies or other antagonists to angiogenic agents as defined above, such as antibodies to VEGF or Angiotensin 2. They additionally include cytotherapeutic agents such as cytotoxic agents, chemotherapeutic agents, growth inhibitory agents, apoptotic agents, and other agents to treat cancer, such as anti-HER-2, anti CD20, and other bioactive and organic chemical agents.
Polypeptide agents may be introduced by expression in vivo, which is often referred to as gene therapy. There are two major approaches for getting the nucleic acid (optionally containing a vector) into the patients cells: in vivo and ex vivo. For in vivo delivery, the nucleic acid is injected directly into the patient, usually at the site where desired. For ex-vivo delivery, the patients cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient either directly or via encapsulation within porous membranes that are implanted into the patient (see U.S. Pat. Nos. 4,892,538 and 5,283,187).
The preferred embodiment of this invention is the delivery of therapeutic molecules from micro drug delivery systems such as liposomes, nanoparticles, biodegradable controlled release polymer matrices, and biodegradable microspheres which are well known in the literature. These have been described briefly in U.S. application Ser. No. 08/816,850.
The agents to be delivered may include one or more small molecules, macromolecules, liposomal encapsulations of molecules, microdrug delivery system encapsulation of therapeutic molecules, covalent linking of carbohydrates and other molecules to a therapeutic molecules, and gene therapy preparations. These will be briefly defined.
xe2x80x9cSmall moleculesxe2x80x9d may be any smaller therapeutic molecule, known or unknown. Examples of known small molecules relative to cardiac delivery include the antiarrhythmic agents that affect cardiac excitation. Drugs that predominantly affect slow pathway conduction include digitalis, calcium channel blockers, and beta blockers. Drugs that predominantly prolong refractoriness, or time before a heart cell can be activated, produce conduction block in either the fast pathway or in accessory AV connections including the class IA antiarrhythmic agents (quinidine, procainimide, and disopyrimide) or class IC drugs (flecainide and propefenone). The class III antiarrhythmic agents (sotolol or amiodorone) prolong refractoriness and delay or block conduction over fast or slow pathways as well as in accessory AV connections. Temporary blockade of slow pathway conduction usually can be achieved by intravenous administration of adenosine or verapamil. [Scheinman, Melvin: Supraventricular Tachycardia: Drug Therapy Versus Catheter Ablation, Clinical Cardiology Vol 17, Suppl. II-11-II-15 (1994)]. Many other small molecule agents are possible, such as poisonous or toxic agents designed to damage tissue that have substantial benefits when used locally such as on a tumor. One example of such a small molecule to treat tumors is doxarubicin.
A xe2x80x9cmacromoleculexe2x80x9d is any large molecule and includes proteins, nucleic acids, and carbohydrates. Examples of such macromolecules include the growth factors, Vascular Endothelial Growth Factor, basic Fibroblastic Growth Factor, and acidic Fibroblastic Growth Factor, although others are possible. Examples of macromolecular agents of interest for local delivery to tumors include angiostatin, endostatin, and other antiangiogenic agents.
A xe2x80x9cLiposomexe2x80x9d refers to an approximately spherically shaped bilayer structure comprised of a natural or synthetic phospholipid membrane or membranes, and sometimes other membrane components such as cholesterol and protein, which can act as a physical reservoir for drugs. These drugs may be sequestered in the liposome membrane or may be encapsulated in the aqueous interior of the vesicle. Liposomes are characterized according to size and number of membrane bilayers.
A xe2x80x9cgene therapy preparationxe2x80x9d is broadly defined as including genetic materials, endogenous cells previously modified to express certain proteins, exogenous cells capable of expressing certain proteins, or exogenous cells encapsulated in a semi-permeable micro device. This terminology is stretched beyond its traditional usage to include encapsulated cellular materials as many of the same issues of interstitial delivery of macrostructures apply.
The term xe2x80x9cgenetic materialxe2x80x9d generally refers to DNA which codes for a protein, but also encompasses RNA when used with an RNA virus or other vector based upon RNA. Transformation is the process by which cells have incorporated an exogenous gene by direct infection, transfection, or other means of uptake. The term xe2x80x9cvectorxe2x80x9d is well understood and is synonymous with xe2x80x9ccloning vehiclexe2x80x9d. A vector is nonchromosomal double stranded DNA comprising an intact replicon such that the vector is replicated when placed within a unicellular organism, for example by a process of transformation. Viral vectors include retroviruses, adenoviruses, herpesvirus, papovirus, or otherwise modified naturally occurring viruses. Vector also means a formulation of DNA with a chemical or substance which allows uptake by cells. In addition, materials could be delivered to inhibit the expression of a gene. Approaches include: antisense agents such as synthetic oligonucleotides which are complimentary to RNA or the use of plasmids expressing the reverse compliment of a gene, catalytic RNA""s or ribozymes which can specifically degrade RNA sequences, by preparing mutant transcripts lacking a domain for activation, or over express recombinant proteins which antagonize the expression or function of other activities. Advances in biochemistry and molecular biology in recent years have led to the construction of recombinant vectors in which, for example, retroviruses and plasmids are made to contain exogenous RNA or DNA respectively. In particular instances the recombinant vector can include heterologous RNA or DNA by which is meant RNA or DNA which codes for a polypeptide not produced by the organism susceptible to transformation by the recombinant vector. The production of recombinant RNA and DNA vectors is well understood and need not be described in detail. Such gene therapy preparations could be delivered in a variety of fluid agents, one of which is phosphate buffered saline.
Details on microencapsulated cells are described in U.S. Pat. No. 5,698,531 and additional details on the delivery of genetic material are described in U.S. Pat. No. 5,704,910. Both of these patents describe the potential of delivering such agents endoluminally within a blood vessel. Neither of these provides a means to deliver such agents at a depth within the heart muscle, and neither of them recognizes the potential of this approach. U.S. Pat. No. 5,661,133 does recognize the potential for delivering genes to the heart, but does not describe the means of delivery other than by injection.
U.S. Pat. No. 5,244,460 issued to Unger describes a method of introducing growth factors over time by delivering them through fluid catheters into the coronary arteries, but this does not result in efficient delivery of these agents to the ischemic tissue. If these or other agents are delivered to the coronary, a region of tissue that is equivalent to that supplied by the artery will receive the therapeutic agents. This may be substantially more tissue than is in need of local drug delivery therapy. Further, if a vessel is occluded, the growth factors will act in the tissue which the coronary arteries successfully perfuse. As the underlying problem of ischemic tissue is poor perfusion, excess growth factor must be delivered in order to obtain the desired effects in the poorly perfused tissue. Further, growth factors may cause unwanted angiogenesis in tissues where inappropriately delivered. The cornea is described by Unger as such a location, but perhaps more critical is inappropriate delivery of these factors to the brain. Further, placement of delivery devices within these coronary arteries as Unger describes will tend to obstruct these arteries and may augment occlusive thrombosis formation. There is a significant need for a means and method of minimizing the amount of growth factors for introducing angiogenesis by delivering these agents only to the site where they are most needed.
In addition to a device for delivering growth factors, there are complications with clinically acceptable procedures where special devices for delivering agents to ischemic tissue will be useful. After opening vessels using PTCA, the vessels often lose patency over time. This loss of patency due to restenosis may be reduced by appropriate pharmacological therapy in the region of the artery. There is a need for new. techniques that will enable pharmacological therapy to reduce the incidence of restenosis.
Arrhythmogenic Sites
Cardiac arrhythmias are abnormal rhythmic contractions of the myocardial muscle, often introduced by electrical abnormalities, or irregularities in the heart tissue, and not necessarily from ischemic tissue.
In a cardiac ablation procedure, the arrhythmogenic region is isolated or the inappropriate pathway is disrupted by destroying the cells in the regions of interest. Using catheter techniques to gain venous and arterial access to the chambers of the heart, and possibly trans septal techniques, necrotic regions can be generated by destroying the tissue locally. These necrotic regions effectively introduce electrical barriers to problematic conduction pathways.
U.S. Pat. No. 5,385,148 issued to Lesh describes a cardiac imaging and ablation catheter in which a helical needle may be used to deliver fluid ablative agents, such as ethanol, at a depth within the tissue to achieve ablation. Lesh further describes a method of delivering a pharmacological agent to the tissue just before performing the chemical ablation procedure to temporarily alter the conduction of the tissue prior to performing the ablation. Such temporary alteration of tissue has the advantage of allowing the physician to evaluate the results of destructive ablation in that region prior to actually performing the ablation. This method of ablation has the advantage that the ablative fluid agents are delivered to essentially the same tissue as the temporary modifying agents. However, with ablative fluid agents it is difficult to control the amount of tissue which is destroyedxe2x80x94especially in a beating heart, and ablative RF energy is in common use because of its reproducible lesions and ease of control. There is a need for an ablation catheter that provides for both temporary modification of tissue conductivity by delivery of therapeutic agents at a depth within the tissue and delivery of RF energy from the same structure within the heart wall that was used to deliver the therapeutic agents.
U.S. Pat. No. 5,527,344 issued to Arzbaecher describes a pharmacological atrial defibrillator and method for automatically delivering a defibrillating drug into the bloodstream of a patient upon detection of the onset of atrial arrhythmias in order to terminate the atrial arrhythmias, and is herein incorporated by reference. By delivering agents to a blood vessel, Arzbaecher requires systemic effects to be achieved in order to terminate the atrial arrhythmias. The advantages of local drug delivery are completely absent from the system described. There is a need for a system and method to transiently treat atrial arrhythmias by local delivery of pharmacological agents which will effect the excitation of the cardiac tissue locally.
There have been many patents describing systems for delivering anti inflammatory agents to the endocardial surface of the heart. Such surface delivery is less viable for regions at a depth within the tissue. Further, because of the volume of fluid moving by the inner surfaces of the heart, higher concentrations may be required at the surface to counteract the effects of dilution. These higher doses result in greater likelihood of problematic systemic effects from the therapeutic agents. Delivering agents within the tissue will minimize the dilution of agents, and decrease the possibility of the agents being delivered to inappropriate sites. This is particularly important with growth factors whose systemic affects are not well documented, just as it is important for antiarrhythmic agents whose pro-arrhythmia systemic effects have been recognized. There is a need for a means to deliver agents to ischemic and arrhythmogenic sites within the myocardium.
The prior art of devices to deliver substances at a depth within the heart is not extensive. U.S. Pat. Nos. 5,447,533 and 5,531,780 issued to Vachon describe pacing leads having a stylet introduced anti inflammatory drug delivery dart and needle which is advanceable from the distal tip of the electrode. U.S. Pat. No. 5,002,067 issued to Berthelson describes a helical fixation device with a groove to provide a path to introduce anti-inflammatory drug to a depth within the tissue. U.S. Pat. No. 5,324,325 issued to Moaddeb describes a myocardial steroid releasing lead whose tip of the rigid helix has an axial bore which is filled with a therapeutic medication such as a steroid or steroid based drug. None of these patents provide a means for site specific delivery of agents as all applications of the drug delivery systems are at the location selected for pacing. None of these has provided a means or method for delivering agents to ischemic or infarcted tissues. Of these, only Vachon and Moaddeb provide a means for effectively delivering the anti-inflammatory agents to a depth within the myocardium. U.S. Pat. No. 5,551,427 issued to Altman describes a catheter system capable of delivering drugs to the heart at a depth within the heart tissue.
U.S. Pat. No. 5,431,649 issued to Mulier describes a hollow helical delivery needle to infuse the heart tissue with a conductive fluid prior to ablation to control the lesion size produced. The system does not have drug delivery capabilities.
None of the prior art provides controlled release matrix delivery down a needle or helix to a depth within the heart tissue. None of the prior art provides for a distally located osmotic pump to deliver agents to a depth within the heart tissue. None of the prior art provides a means of delivering agents transiently to a depth within the heart tissue upon demand. None of the prior art provides a means to clear the catheter system of one drug and effectively replace it with a second drug. None of the prior art provides a low impedance conductor to the drug delivery structure for performing ablation after the delivery of a drug. None of the prior art includes the use of macromolecular controlled release matrices such as ethylene vinyl acetate co-polymer to deliver agents with large molecular weights to a depth within the heart tissue.
Local drug delivery provides many advantages. Approaches for local delivery of agents at a depth within a tissue enables the delivery of drugs to sites where they are most needed, reduces the amount of drugs required, increases the therapeutic index of the particular dosing regime, and increases the control over the time course of agent delivery. These, in turn, improve the viability of the drugs, lower the amount (and cost) of agents, reduce systemic effects, reduce the chance of drug-drug interactions, lower the risk to patients, and allow the physician to more precisely control the effects induced. Such local delivery may mimic endogenous modes of release, and address the issues of agent toxicity and short half lives. Approaches for local drug delivery using a catheter based system with a distally located tissue penetrating element have applications in organs such as the heart, pancreas, esophagus, stomach, colon, large intestine, or other tissue structure to be accessed via a controllable catheter.
Local drug delivery to the heart is known. In U.S. Pat. No. 5,551,427, issued to Altman, implantable local drug delivery at a depth within the heart is described. The patent shows an implantable helically coiled injection needle which can be screwed into the heart wall and connected to an implanted drug reservoir outside the heart. This system allows injection of drugs directly into the wall of the heart acutely by injection from the proximal end, or on an ongoing basis by a proximally located implantable subcutaneous port reservoir, or pumping mechanism. The patent also describes implantable structures coated with coating which releases bioactive agents into the myocardium. This drug delivery may be performed by a number of techniques, among them infusion through a fluid pathway, and delivery from controlled release matrices at a depth within the heart. Controlled release matrices are drug polymer composites in which a pharmacological agent is dispersed throughout a pharmacologically inert polymer substrate. Sustained drug release takes place via particle dissolution and slowed diffusion through the pores of the base polymer. Pending applications Ser. No. 08/816,850 by Altman and Altman, and Ser. No. 09/131,968 by Altman and Ser. No. 09/177,765 by Altman describe and Ser. No. 09/257,887 by Altman and Altman describe some additional techniques for delivering pharmacological agents locally to the heart. The techniques described herein are all incorporated by reference.
Recently, local delivery to the heart has been reported of therapeutic macromolecular biological agents by Lazarous [94 Circulation, 1074-1082 (1996)], plasmids by Lin [82 Circulation 2217-2221 (1990)], and viral vectors by French [90 Circulation 2414-2424 (November 1994)] and Muhlhauser [3 Gene Therapy 145-153 (1996)]. March [89 Circulation 1929-1933 (May 1994)] describes the potential for microsphere delivery to the vessels of the heart, such as to limit restenosis.
U.S. Pat. No. 4,296,100 issued to Franco describes direct injection of FGF into the heart but specifically does not call out catheter techniques. U.S. Pat. No. 5,693,622 issued to Wolff describes promoters for gene therapy to the heart, but does not enable the delivery of DNA sequences through either vascular or cardiac catheter, or by the injection into the interstitial spaces of the heart.
U.S. Pat. Nos. 5,807,395; 5,431,649 and 5,405,376 issued to Mulier and U.S. Pat. No. 5,385,148 issued to Lesh describe helical needles for use during an ablation procedure, and are limited to ablation catheter uses. They also require the presence of high conductors capable of carrying energy to perform ablation, and do not provide for instruction on how to access different regions of the myocardium and confirm the placement of a device prior to the delivery of fluid agent, nor do they describe a means for guaranteeing that a precise dose is delivered of a particular fluid agent. U.S. Pat. No. 5,840,059 issued to March describes a means of delivering therapeutic agents into a channel within the heart, but suffers the serious limitation in that the material will likely not be retained in the channels. The viscous carrier suggested by March to help retain the material within the channels poses substantial risk as embolic material should it escape from the channels and be released into the endocardial chamber.
The devices and methods described below provide for the delivery of small doses of therapeutic agents within the body, in particular the heart. The catheters described below include a distal helical coil or other fixation and penetrating element which can be operated from the proximal end of the catheter to engage and penetrate the myocardium. Once delivered to the inside of the heart, the catheter can be used to inject small doses of therapeutic agents to the myocardium. The drug delivery system of the catheter allows for precise control of the dose injected into the heart wall.
The devices may be used to administer a number of therapeutic agents followed by additional therapeutic agents or passive agents intended to ensure that the intended dose is delivered notwithstanding the dead space of the catheter. Therapeutic agent in the catheter dead space is flushed from the dead space into the heart. Calibrated therapeutic agent reservoirs account for the dead space, and passive agent reservoirs provide a ready source for flushing fluid. The reservoirs may be filled prior to a catheterization, and inserted into a catheter proximal handle so that they are easily operated during the catheterization. The reservoirs are connected to the drug delivery lumen of the infusion catheter through a valve which may be selectively operated to align one or the other reservoir to the drug delivery lumen of the catheter. Additionally, the drug reservoirs may be connected to the valve through flexible distensible lengths of tubing, permitting easy manipulation of the reservoirs for filling and placement in the proximal handle.
The catheter described herein can be used for a number of procedures, including local delivery of angiogenic agents, controlling heart rate during heart procedures and transmyocardial revascularization.